Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation

Abstract

The validation of drug targets in malaria and other human diseases remains a highly chal- lenging process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malar- ial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target’s function in vivo. Thus, new approaches to identify a protein’s function in vivo are required to provide target validation in the drug discovery process. Oligomerisation is the assembly of two or more copies of a single protein into one object and this self-assembly is present in approximately one third of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interface regions of essential plasmodial proteins have not yet been systematically explored or exploited as a method to dissect biochemical pathways in vivo. This mini review will describe initial efforts to exploit oligomerisation surfaces in drug target validation.